An estimated 39 million people are infected with human immunodeficiency type-1 (HIV-1) world-wide (Piot et al., Nature, 2001, 410:968-973). The majority of infected people live in the developing world with limited treatment resources. Antiretroviral therapy (ART) has significantly reduced HIV-1 disease morbidity and improved life expectancy. However, a number of factors make eradication of HIV-1 by antiretroviral therapy more difficult. These include difficulties adhering to complex antiretroviral regimens of drugs with low margins for pharmacokinetic deviation, identification of cellular reservoirs that survive despite ART, and the potential existence of sanctuary sites within the body where antiretroviral drug levels are not optimal. Additionally, the economics of drug treatment, treatment failures due to the development of resistance, and limited global access has prevented world-wide use of antiretroviral therapy (Chen et al., AIDS Trd Hum Retroviruses, 2002, 18:900-916, Chulamokha et al., J. Neurovirol., 2005, 11:76-80). Dosing regimens that require multiple daily dosing with diet considerations and antiretroviral therapy side effects have compromised the achievement of longterm HIV-1 suppression in infected patients (Fellay et al., Lancet, 2001, 358:1322-1327).
The CD4+ T lymphocyte is the major target for infection by HIV-1. Cells of the mononuclear phagocyte system also serve as a reservoir for HIV. Macrophages are mature, non-proliferating and immunologically active cells that can be productively infected with HIV-1 and HIV-2 (Gartner et al., Science, 1986, 233:215-219, Kuhnel et al., Proc Natl Acad Sci USA, 1989, 86:2382-2387, Nicholson et al., J Immunol., 1986, 137:323-329, von Briesen et al., Res Virol., 1990, 141:225-231). Altered cellular functions in the macrophage population may contribute to the development and clinical progression of AIDS.
Evidence has accumulated that cells of the macrophage lineage are vectors for the transmission of HIV-1. The placental macrophage is likely to be the primary cell type responsible for vertical transmission of HIV-1 (McGann et al., J Infect Dis., 1994, 169:746-753). An important property of HIV-1 for mucosal transmission is the ability to infect macrophages (Milman et al., AIDS Res. Hum Retroviruses, 1994, 10:1305-1312). Because of the important role of cells of the monocytes/macrophage (Mo/Mac) lineage in the pathogenesis of HIV-1, fully effective antiretroviral therapy must react with Mo/Mac in addition to other targets.
Many promising compounds suffer from poor physiochemical properties leading to poor solubility and biodistribution. Such properties limit drug-receptor interactions to cause desired effects. For example, proteins and peptides could be new drug candidates but suffer from low oral absorption in the gastrointestinal tract.
Combination antiretroviral therapy has significantly reduced HIV-1 disease morbidity and improved life expectancy. Combinations of drugs from different classes have proven to offer sustained efficacy and long-term safety. Controlling viral replication allows at least partial reconstitution of the immune system. However, despite sustained viral suppression for prolonged periods, eradication of HIV-1 from patients has not been achieved.